AUTHOR=Mušo Milan , Bentley Liz , Vizor Lucie , Yon Marianne , Burling Keith , Barker Peter , Zolkiewski Louisa A. K. , Cox Roger D. , Dumbell Rebecca 

TITLE=A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.953199

DOI=10.3389/fphys.2022.953199

ISSN=1664-042X

ABSTRACT=<p><bold>Background:</bold> Increased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The <italic>TBX15</italic>-<italic>WARS2</italic> locus has consistently been associated with increased WHR. Previous study of the hypomorphic <italic>Wars2</italic><sup><italic>V117L/V117L</italic></sup> mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting <italic>Wars2</italic> could be a potential modulator of fat distribution and WAT browning.</p><p><bold>Methods:</bold> To test for differences in browning induction across different adipose depots of <italic>Wars2</italic><sup><italic>V117L/V117L</italic></sup> mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed <italic>Wars2</italic><sup><italic>V117L/V117L</italic></sup> mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age.</p><p><bold>Results:</bold> The chow-fed <italic>Wars2</italic><sup><italic>V117L/V117L</italic></sup> mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the <italic>Wars2</italic><sup><italic>V117L/V117L</italic></sup> mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT: iWAT ratio.</p><p><bold>Conclusion:</bold> Severe reduction of <italic>Wars2</italic> gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.</p>